title: Wnt/β-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells.
abstract: Facioscapulohumeral muscular dystrophy is a dominantly inherited myopathy associated with chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4. DUX4 is encoded within each unit of the D4Z4 array where it is normally transcriptionally silenced and packaged as constitutive heterochromatin. Truncation of the array to less than 11 D4Z4 units (FSHD1) or mutations in SMCHD1 (FSHD2) results in chromatin relaxation and a small percentage of cultured myoblasts from these individuals exhibit infrequent bursts of DUX4 expression. There are no cellular or animal models to determine the trigger of the DUX4 producing transcriptional bursts and there has been a failure to date to detect the protein in significant numbers of cells from FSHD-affected individuals. Here, we demonstrate for the first time that myotubes generated from FSHD patients express sufficient amounts of DUX4 to undergo DUX4-dependent apoptosis. We show that activation of the Wnt/β-catenin signaling pathway suppresses DUX4 transcription in FSHD1 and FSHD2 myotubes and can rescue DUX4-mediated myotube apoptosis. In addition, reduction of mRNA transcripts from Wnt pathway genes β-catenin, Wnt3A and Wnt9B results in DUX4 activation. We propose that Wnt/β-catenin signaling is important for transcriptional repression of DUX4 and identify a novel group of therapeutic targets for the treatment of FSHD.
authors.affiliation: Department of Pediatrics.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Block
authors.forename: Divya
authors.initials: D
authors.lastname: Narayanan
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Amell
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Petek
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Davidson
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: C121257:DUX4L1 protein, human; C532958:Dux4 protein, mouse; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering